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Publication Number
US-8067448-B2
Publication Date
2011-11-29
Expiration Date
Abstract
This invention provides compounds of formulas I, Ia, Ib, Ic, Id, Ie, and or salts thereof, pharmaceutical compositions comprising a compound of formulas I, Ia, Ib, Ic, Id, Ie, and a pharmaceutically acceptable excipient, methods of modulating the androgen receptor, methods of treating diseases beneficially treated by an androgen receptor modulator (e.g., sarcopenia, prostate cancer, contraception, type 2 diabetes related disorders or diseases, anemia, depression, and renal disease) and processes for making compounds of formulas I, Ia, Ib, Ic, Id, Ie, and intermediates useful in the preparation of same.
Core Innovation
The patent describes selected substituted benzonitrile and benzo[b]thiophene compounds that include a 1,3,4-oxadiazol-2-yl group and a hydroxypropylamino stereochemical framework. The compounds are explicitly defined by their structures, including variations in aryl substitution patterns and benzonitrile or benzo[b]thiophene cores, and pharmaceutically acceptable salts thereof. The specification context ties these scaffold compounds to androgen receptor modulation.
The document also provides synthetic transformations leading to oxadiazole-containing benzonitrile and benzo[b]thiophene targets and related intermediates, including benzohydrazide intermediates and cyclization to the 1,3,4-oxadiazole-containing products. The described products include defined stereochemistry such as (1R,2R), (1R,2S), (2R,3R), and (2R,3S) motifs. Reported characterization includes isolated yields and 1H NMR data for produced species.
Further transformations described in the document include protection and deprotection using TBS/TBDMS and tetrabutylammonium fluoride, as well as acylation, sulfonation, and esterification on the scaffold. The document additionally describes oxadiazole formation using PS-BEMP and p-TsCl or related conditions, and includes example compounds with phenyl, substituted phenyl, and other aryl groups on the oxadiazole ring. Reported characterization includes 1H NMR, LRMS, and melting point where provided.
Claims Coverage
The claim coverage centers on one independent claim that lists selected compounds and provides coverage for pharmaceutically acceptable salts, with additional coverage via pharmaceutical composition and androgen-receptor modulation methods. Three inventive features are present across the claim family.
Selected substituted benzonitrile and benzo[b]thiophene oxadiazole compounds
A compound selected from specific substituted benzonitrile and benzo[b]thiophene-7-carbonitrile structures bearing a hydroxypropylamino linkage and a 1,3,4-oxadiazol-2-yl substituent with specified aryl groups, including pharmaceutically acceptable salts thereof.
Pharmaceutical composition comprising the selected compound with pharmaceutically acceptable excipients
A pharmaceutical composition comprising a compound according to the selected compound set together with at least one pharmaceutically acceptable excipient.
Administering to modulate an androgen receptor in a cell
A method of modulating an androgen receptor in a cell by administering a compound according to the selected compound set or a pharmaceutically acceptable salt thereof.
Identifying androgen receptor modulators by contacting and monitoring
A method of identifying compounds capable of modulating an androgen receptor by contacting an androgen-receptor-expressing cell with a test compound or a pharmaceutically acceptable salt and monitoring the effect on the cell.
Overall, the claims protect the enumerated substituted benzonitrile and benzo[b]thiophene oxadiazole compounds with specified stereochemistry, together with pharmaceutical compositions containing those compounds and methods that use them to modulate or identify androgen receptor activity in cells.
Stated Advantages
AR-binding affinity is characterized using IC50 values reported in Table 1.
In vivo Rat Herschberger assay results show organ-weight effects and comparisons to sham-operated animals.
Tissue selectivity is discussed, including effects associated with levator ani versus prostate/seminal vesicle.
Documented Applications
AR-binding assessment reporting IC50 values in Table 1.
In vivo biological evaluation using the Rat Herschberger assay in orchidectomized rats, with organ-weight effects reported and compared with sham-operated animals.
Use-context discussion of tissue selectivity, including levator ani stimulation versus prostate/seminal vesicle effects.
Methods for modulating an androgen receptor in a cell by administering the selected compounds or pharmaceutically acceptable salts.
Methods for identifying compounds capable of modulating an androgen receptor by contacting androgen-receptor-expressing cells with a test compound and monitoring the effect on the cell.
Treating sarcopenia, prostate cancer, contraception, type 2 diabetes related disorders, anemia, depression, and renal disease using an androgen receptor modulator.
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